Podcasts about heart failure hospitalization

Commentary by Dr. Candice Silversides

Dr. Centor discusses the indications for prescribing sodium-glucose cotransporter-2 inhibitors for patients with heart failure with observed ejection fraction with Dr. Sarah Adie.

Commentary by Dr. Valentin Fuster

Commentary by Dr. Greg Hundley

Overview: Although heart failure contributes to millions of hospitalizations in the United States each year that significantly impact patient prognosis, treatment is often focused on managing symptoms rather than on optimizing therapy.1,2 In this episode, featuring cardiologist Dr Javed Butler of the University of Mississippi, we will discuss best practices for navigating a heart failure hospitalization, including assessment of the patient’s clinical trajectory and optimization of guideline-directed medical therapy. Faculty: Javed Butler, MD, MPH, MBA

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. You know that problem we have with the development of calcification of the aortic valve, the aorta, etcetera with hemodialysis? Well, our feature is going to talk about the results of a randomized phase 2B study to address this. But first, how about if you get us started with a couple of your papers? Dr Carolyn Lam: In fact, it is a couple of papers and they're both related to hypertension. So in the first one, we know that exercise is associated with a lower incidence of hypertension, but what's the association of excessive levels of exercise in the incidence of hypertension? This question was examined by Dr Andersen from Uppsala University Hospital and colleagues, who compared the incidence of hypertension among almost 207,000 participants in a long-distance cross-country skiing event and more than 505,500 persons randomly sampled from the general population who are matched to the skiers on age, sex, and place of residence. Dr Greg Hundley: I love skiing! I want to be in the match group. Tell me, now, how long was this distance that they had to cover? Dr Carolyn Lam: Ah ha. Now the long distance event was really long. It was the Vasaloppet. I hope I pronounced that right, but it's a 45 to 90 kilometer skiing race. So participation, I'm sure you want to hear this, participation was associated with a 41% lower incidence of hypertension over the next eight years, compared to non-participation. And the better the performance in terms of percent of winning time, the lower the incidence of hypertension. If the observed associations are causal, it really adds to the list of beneficial effects of high, or even very high physical fitness. I can see you smiling, Greg. Dr Greg Hundley: This is your confirmation that the AHA wants to send us to Norway to do one of these recordings. Dr Carolyn Lam: Well, this next paper asked the question, what is the association of cumulated blood pressure exposure from young adulthood to midlife with gait and cognitive function in midlife. This is from Dr Mahinrad from Northwestern University Feinberg School of Medicine and colleagues who included 191 participants from the coronary artery risk development in young adults’ study, which is a community-based cohort of young individuals followed over 30 years. Cumulated blood pressure was calculated as the area under the curve for baseline up to year 30 exam and gait and cognition were assessed at the year 30 exam. Cerebral white matter hyperintensity was available at year 30 in a subset of participants who underwent MRI. Dr Greg Hundley: I heard that MRI word. So what did they find Carolyn? Dr Carolyn Lam: They found cumulative exposure to higher blood pressures from young adulthood to midlife, even at levels below the clinical definition of hypertension, was associated with worse gait and worse cognitive function in midlife. The impact of cumulative levels of blood pressure exposure was independent of other vascular risk factors during a follow-up period of over 30 years, and the higher burden of midlife cerebral white matter hyperintensity on MRI, Greg, moderated the association of cumulated blood pressure exposure with gait but not with cognitive function. Dr Greg Hundley: You've got me convinced we now have to go to Norway. But what did the authors think were the clinical implications of their study? Dr Carolyn Lam: Well, here it is. The deleterious effect of elevated blood pressure on brain structure and function may begin during early adulthood and this really emphasizes the need for all primordial, if you may, prevention of high blood pressure. But also reconsidering individual levels of blood pressure for the diagnosis of hypertension. Furthermore, gait may be an earlier measure of hypertensive brain injury than cognition. Now these issues are discussed an editorial by Angela Jefferson from Vanderbilt University Medical Center. Dr Greg Hundley: Very nice, Carolyn. Well, I'm going to take another sort of twist on hypertension. My paper is from Dr Thomas Thum from the Hanover Medical School and is really looking at the relationship between cardiac fibrosis and diastolic dysfunction. So the study sought to identify anti-fibrotic drug candidates by functional screening of 480 chemically diverse natural compounds found in human cardiac fibroblasts. Dr Carolyn Lam: Ooh, interesting. And what did they find? Dr Greg Hundley: What they found is using multiple in vitro fibrosis assays and stringent selection algorithms, the authors identified the steroid bufalin, also seen in Chinese toad venom, and the alkaloid lycorine, from the Amaryllidaceae species, to be effective anti-fibrotic molecules, both in vitro and in vivo, leading to improvement in diastolic function in two hypertension dependent rodent models of cardiac fibrosis. In addition, administration of these agents at effective doses did not change plasma damage markers, nor the morphology of the kidney and liver. And therefore, it's kind of an early first toxicological safety study. Dr Carolyn Lam: Fascinating. Not just in the findings and the methods, and who knew we'd be talking about Chinese toad venom on this podcast, Greg? Okay. But let me tell you about what's more in this issue. So, there is a research letter by Dr Djoussé, and it is entitled Supplementation with Vitamin D and/or Omega-3 Fatty Acids and the Incidence of Heart Failure Hospitalization. And this one is a letter from the VITAL-Heart Failure ancillary study of the parent VITAL trial. I'm sure I've got everyone's attention. (You) Got to read that letter. The next is an On My Mind, by Dr Joe Hill, and is entitled, very intriguingly, Can HFpEF and HFrEF Co-exist? Basically accumulating evidence has revealed that the pathophysiologic mechanisms driving HFrEF and HFpEF are distinct, but this On My Mind paper asks can they coexist? Is it possible to identify subjects who harbor pathophysiological elements of both syndromes simultaneously, and if so, we may find that targeting specific pathways is beneficial and in depth characterization of specific subsets of patients might help overcome the limitations of an ejection fraction driven approach. Dr Greg Hundley: Very interesting, Carolyn. I've got some letters from the mailbox, and the first letter is regarding SGLT2 inhibitors in cardiac hypertrophy and the corresponding author is Professor Kazushi Tsuda from Kansai University of Health Sciences. Another letter, from the corresponding author Dr Renato Lopes from Duke University Medical Center in Durham, evaluates stent thrombosis in patients with atrial fibrillation undergoing coronary stenting from the AUGUSTUS trial. And our own Tracy Hampton provides an update on cardiology news features. And John Warner, from UT Southwestern, the prior American Heart Association president, discusses his journey through healthcare reform. And then finally, our own Sarah O'Brian provides highlights from other journals in the Circulation family related to high points in cardiovascular disease. Well, Carolyn, how about on to dialysis and calcification? Dr Carolyn Lam: Can't wait. Let's go. Our feature discussion today, we will be focusing on patients with end-stage kidney disease. And we know that in these patients, the high cardiovascular morbidity and mortality could partially be due to extensive cardiovascular calcification. Well, our feature paper today is the first double blind placebo-controlled phase 2B trial that tests intravenous myo-inositol hexaphosphate, a novel strategy to inhibit the formation and growth of hydroxyapatite and therefore reduce calcification in these patients. I won't tell you more. I'll leave that to the corresponding author, Professor Paolo Raggi, from University of Alberta, and I'm also so pleased to have with us our editor for digital strategies and associate editor Dr Amit Khera from UT Southwestern. So Paolo, please tell us about SNF472 and your very novel trial. Prof Paolo Raggi: As you correctly stated, patients with end stage renal disease have phenomenally high morbidity and mortality, particularly cardiovascular, and they also manifest extreme calcification on the cardiovascular system. Both the valves and the vessels are very heavily calcified. There's a very clear impression throughout the literature that calcification contributes, no doubt, to the high morbidity mortality with these patients. SNF472 is a derivative of a natural product that is only present in nature in sub molecular quantities and essentially is administered intravenously and the mechanism of action is quite simple. It keeps calcium and phosphorous molecules separate. In other words, it doesn't allow crystallization of calcium and phosphate into what we call hydroxyapatite, or amorphous calcium crystals. This, hopefully, was developed, this product was developed, to inhibit the final step of calcification. Everything comes down, no matter what the promoting event is, to crystallization of calcium and phosphorus. Therefore, if we were able to stop the final event, hopefully you will be able to inhibit further calcification, and that's what we tested in this particular article, in this particular study. Dr Carolyn Lam: Oh Paolo, I just love the way you described that. Very, very crystal clear, if you don't mind the pun. But could you please let us know, so a phase 2B trial, does that mean a surrogate outcome, duration of treatment, number of patients? How about telling us a little bit about the trial? Prof Paolo Raggi: So, the trial involved recruiting three different groups of patients. One would be treated with placebo and two other cohorts would be treated with either 300 milligrams of SNF472 three times a week or 600 milligrams of SNF472 three times a week. The product is injected intravenously into the dialysis line. Therefore, the patients do not have to remember to take a pill or inject themselves. Actually, it's perfect, if you will, compliance because all they have to do is come to their dialysis session and they receive it during dialysis. The study therefore, it was a relatively small study, but enough to prove our point. Three groups were recruited, about 90 patients each, and the two treatment arms at 300 milligrams and the 600 milligrams, were combined as a single group for the purpose of reporting the primary results. The follow up was at one year, so these patients were submitted to CT scanning of the chest without contrast for measurement of calcification only at baseline and then again at 52 weeks. In the intention to treat group, patients were included if they had a baseline scan and at least one follow-up scan at some point during the study. These are very sick patients and sometimes are referred for transplant. Sometimes they withdraw from studies. So, we asked everybody to have a second scan if they needed or wanted to withdraw before the 12 month mark was reached. That's for the intention to treat analysis. And then we need some confirmatory analysis on patients who actually did have the baseline in an actual 12 months scan and received the entire year treatment with these two drugs, with a drug or placebo. Dr Carolyn Lam: That's great and please tell us the results. Prof Paolo Raggi: The results were, in our minds, very exciting. And let me first say, that in all the literature that looked at what is the average progression of calcification in the general population, it's anywhere between 10 to 15% per year. For the person with calcium in the coronary arteries, there's an expected progression about 10 to 15%. All the publications in patients with renal failure and undergoing dialysis, show the progression of anywhere between 25 and 35%, so these people are not only more calcified, these patients also progressing very fast. In the particular trial that we reported in Circulation, we demonstrated on average, a progression of 20% in the group receiving placebo and about 11% in the group receiving SNF472. So, there was about a 45% slowing of progression in the treated group compared to the placebo group.   Interestingly enough, we saw a slower progression unusual in the placebo group. As of today, many more treatments are available to patients with end stage renal disease that were not available when the original studies that I mentioned earlier were conducted. So, the 25 to 35% progression that we saw 15 years ago, it's now slowed, you notice, to a 20% progression in these patients, but SNF472 was even more effective at further slowing that progression. Dr Carolyn Lam: Well, congratulations first and foremost on a very successful and really striking and novel results. Well, Amit there's so much to discuss I don't even know where to start. But first, maybe can I bring you in by saying, so what, is Circulation now publishing renal papers? Dr Amit Khera: The answer is absolutely yes. So first I want to congratulate Dr Raggi on a fantastic paper. This was a concomitant late breaking science at the American Heart Association Sessions; so, we always try to think of timely and exciting topics and appreciate working so closely with this group to bring this across the finish line. At Circulation, one thing we've been working on is something called Bridging Disciplines, where purposefully we appreciate the heart is not in isolation and not in a box by itself, but within a larger system, a body system. So, we really enjoy these types of papers that cross disciplines and there's an outstanding editorial by Susan Hedayati, from UT Southwestern who's a nephrologist, who weighed in here as well. So we certainly really value these types of papers in Circulation. Prof Paolo Raggi: I have to say, working with Circulation was amazing. You know, you get a great job and so fast. It was an incredible, actually. Dr Amit Khera: Obviously, the results speak for themselves that the study was positive, and we certainly see this diminishing the vascular classification and certainly you've been, for decades now, an expert in vascular calcification and coronary imaging. And you know, the question that always comes up is, what are the implications here? Now, on one side, especially with the coronaries, you think this would be favorable, you get less obstructive disease, perhaps less ischemic heart disease. But there's always been this debate if calcium's a good or bad thing in terms of plaque stabilization, so what are your thoughts on what ends up being the clinical ramifications of this down the road? Prof Paolo Raggi: Well of course, as we clearly stated in the paper, this has to be followed by some sort of clinical outcome study. So, it is only speculating at this point as to what the benefit might be. But more specifically about your question, I think that there is a misinterpretation of what calcification means in general. And honestly, I would prefer not to have calcification in my cardiovascular system if I had the choice. Many believe, and it's possibly true to a degree, that calcification comes in to repair the plaque and there's some sort of repair mechanism, but we have shown very clearly that the greater the calcification burden, the higher the probability of cardiovascular morbidity mortality. And therefore, it is not benign to have cardiovascular calcification in general.   In the case of the patients with end stage renal disease, calcification is not limited to the atherosclerotic plaque. It extends to the thickness of the entire vessel wall and it's well known that patients with end stage renal disease have severe calcification of the media as well as the intima. This obviously causes a series of other problems, such as stiffening of the vessels and therefore reduce compliance and in the long run, many profusion issues to multiple organs, even in the absence of luminal stenosis. A stiff vessel does not comply with what it's supposed to be doing. It is not allowing proper profusion of an end organ and many have demonstrated that also increases the work of the heart, pumping against very rigid plumbing, if you want to put it that way and simply, and therefore may induce left ventricular dysfunction in the long run, arrhythmias if a patient develops left ventricular hypertrophy and fibrosis. So, I think that there's a cascade of events that goes beyond and above just the single plaque, atherosclerosis, calcification. I think that calcification in general, and especially in patients with end stage renal disease, is a whole marker, very high risk of complications. Dr Amit Khera: Thanks for that clarification. I think first and foremost, it's so helpful to think beyond just isolated luminal stenosis and sort of all the maladaptive aspects of vascular calcification in patients with end stage renal disease. And that leads to the next thing in your paper, which I thought was also really interesting, which was the aortic valve calcification. We certainly appreciate that focus on aortic stenosis as of late with the new therapies, but you know particularly in patients with end stage renal disease, it becomes a very complex issue. And you saw some abating of this vascular calcification in the aorta as well. Tell us a little bit about what you think the implications of that would be. Prof Paolo Raggi: So first, a word of caution that the trial was not powered to demonstrate specifically an effect on aortic valve. However, we did demonstrate a beautiful effect on the slowing of the aortic valve calcification as well. It's exciting! I think that it's something that needs to be pursued further and I hope future studies, and definitely is the first time that anything has demonstrated an effect on aortic valve calcification. I'm very well aware of other studies that have attempted, for example, use of statins to slow the progression of valvular calcification and in essence, were completely negative. Patients with end stage renal disease, very severe valvular abnormalities, very, very severe, very important valvular dysfunction as a consequence of massive calcification on the annulus and the leaflets more so of the aortic valve, but also the mitral valve. So this could definitely be a signal for an excellent potential and unexpected if you will, a secondary outcome of this treatment. I believe that in affecting valvular calcification in patients with end stage renal disease would be, could have potentially a massive effect from the point of view of lowering the cardiovascular event rate. Dr Carolyn Lam: May I chime in with a quick question? What were adverse effects like? Prof Paolo Raggi: This particular drug actually was associated with the same exact rate of adverse effect as placebo. In other words, we didn't see anything at all that was alarming. There was one patient that had been reported by the investigator as potential side effect of the drug. They reported something, I think it was like acute hepatic failure, but when the case was clearly analyzed by the DMV, we actually assessed dictation as being a case of cholecystitis had been incorrectly labeled, we believe. And except for that one case, there essentially were no side effects, no adverse effects from treatment. In fact, although it was not powered for those outcomes, there was a lower morbidity and mortality with the SNF472 and then with placebo. Dr Carolyn Lam: I really like that and was really struck by your pointing out a little bit earlier, the ease of administration as part of hemodialysis. That was very nice. Amit, I'm going to give you the final words and questions if I may. Dr Amit Khera: As expected, this has been an exciting podcast and as much as I've read this paper and looked at it in detail, I learned a lot more as I had anticipated. My question for you, Paolo, now, is what's the next step? This is a phase 2B study. What's the next step in the development or evaluation of this compound and where are you going with this? Prof Paolo Raggi: There are a few sub analysis that we haven't yet looked at in this particular study that we just reported. One of the things that we are definitely interested in is to evaluate the effect on bone. As you can imagine, it is true that this particular drug has a wonderful effect on vascular calcification, but the next question is, did it do anything adverse to the bone? It's a logical question but I feel that most likely the answer is going to be a resounding no. But, besides that, the further development of this drug is obvious in my mind. It will have to be addressed in a proper, randomized clinical trial to address some of the clinical questions that we all have. Is this reducing the cardiovascular events? Be it when we need, we will decide together what those cardiovascular events would look like. But obviously myocardial infarction, congestive heart failure, admission for unstable angina, cardiovascular deaths in general, those are going to be very important questions to be answered in a further step. Before we get there, there are a few other questions that we have for the drug itself from this particular 2B study that we can still look at. Dr Amit Khera: Excellent. Looking forward to those subsequent analyses. Dr Carolyn Lam: Thank you and we look forward to the next publication on Circulation. Dr Amit Khera: Absolutely. Dr Carolyn Lam: I'm sure the audience is actually looking forward to more such discussions as these. Remember, you've been listening to Circulation on the Run.   Dr Greg Hundley: This program is Copyright The American Heart Association 2020.  

Commentary by Dr. Valentin Fuster

Dr Gregory Hundley:       Welcome everyone to the June 18th edition of Circulation on the Run. I am Dr Greg Hundley, Professor of Internal Medicine and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.                                                 In today's issue we're deviating from our common format due to some scheduling difficulties. So, rather than our traditional coffee chat in this program I'm going to have a large gulp of coffee and present results from several exciting papers. Then we'll turn over the second half of our program to Dr Carolyn Lam for our feature discussion.                                                 Now, I promise this is a one-time deviation and we will return to our common chat format in early July. But, before I launch into my presentations I did want to introduce what will transpire with Carolyn. She will be discussing an exciting paper from the Adelaide Medical School at the University of Adelaide in Australia.                                                 Some have wondered whether the persistence of a patent arterial venous fistula post-kidney transplant may contribute to ongoing maladaptive cardiovascular remodeling. To address this issue Carolyn will be discussing with authors whether ligation of this AV fistula may reverse this maladaptive remodeling. And like you, I'm excited to listen to that discussion. But before that let me review several of the other distinctive papers on this issue.                                                 The first one is entitled “Individual Treatment Effect Estimation of Two Doses of Dabigatran on Stroke and Major Bleeding in Atrial Fibrillation.” They are the results from the RE-LY trial. The corresponding author is Professor Frank Visseren from the University Medical Center of Utrecht in Utrecht University.                                                 The study emanates from the randomized evaluation of long-term anticoagulation therapy or the RE-LY trial. In which high dose dabigatran, that's 150 milligrams twice daily, was found more effective in prevention of ischemic stroke and systemic embolism than low dose dabigatran which is 110 milligrams twice daily.                                                 But this occurred at that expense of an increased risk of gastrointestinal bleeds. Importantly however, the absolute treatment effect of dabigatran in both doses, likely differs between individuals. And therefore, individual treatment effect estimation has the potential to identify patients who have a favorable trade off and absolute benefit and harm from dabigatran compared with no treatment, and to select the optimal dose for each individual patient.                                                 So in this study, the investigative team derived and validated a prediction model for ischemic stroke and systemic embolism and major bleeding in patients with atrial fibrillation from three treatment arms of the RE-LY study. They had 11,955 individuals in the derivation cohort and 6,158 in the validation cohort. And they evaluated the patient characteristics of sex, age, smoking, anti-platelet drugs, prior vascular disease, diabetes, blood pressure, estimated glomerular filtration rate, and hemoglobin. Dr Gregory Hundley:       Well, what were the results? Well the five-year absolute risk reduction, for ischemic stroke and systemic embolus minus the five-year absolute risk increase for major bleeding, when comparing the high to the low dose of dabigatran yielded a net benefit in 46% of patients. And therefore, the authors conclude that the absolute treatment benefits and harms of dabigatran in atrial fibrillation can be estimated based on readily available patient characteristics.                                                 And perhaps down the road such treatment effect estimations can be used for shared decision making before starting dabigatran treatment and to determine its optimal dose of administration. Well, how 'bout that? And let's go on to the second paper entitled “Empagliflozin and the Risk of Heart Failure Hospitalization in Routine Clinical Care: A First Analysis from the Empagliflozin Comparative Effectiveness and Safety, or EMPRISE Study.                                                 And the corresponding author for this study is Elisabetta Patorno from Brigham and Women's Hospital in the Harvard Medical School. So, as a background in a different study to this, the EMPA-REG OUTCOME trial showed that Empagliflozin an SGLT2 inhibitor was found to reduce the risk of hospitalization for heart failure by 35% on top of standard of care in patients with Type 2 diabetes and established cardiovascular disease.                                                 Well, the current study, The Empagliflozin Comparative Effective and Safety or EMPRISE Study was designed to assess empagliflozin's effectiveness, safety, and health care utilization in routine care from the period of time between August of 2014 through September of 2019. And the author's report on the first interim analysis in which they investigated the risk of hospitalization for heart failure among Type 2 diabetic patients initiating empagliflozin vs. sitagliptin.                                                 The investigators used two commercial and one federal Medicare claims data source from the U.S. and identified a one-to-one propensity score matched cohort of 16,443 pairs of Type 2 diabetes patients that were greater than 18 years of age initiating empagliflozin or sitagliptin. The average age of the participants was approximately 59 years.                                                 And almost 54% of the participants were males and approximately 25% had records of existing cardiovascular disease. So compared to sitagliptin the initiation of empagliflozin decreased the hospitalization for heart failure risk by 50% over a mean follow-up of 5.3 months. And the results were consistent in patients with and without baseline cardiovascular disease for both the empagliflozin 10 milligram or 25 milligram daily dose. Or analysis comparing empagliflozin vs. dipeptidyl peptidase-4 inhibitor class all comers.                                                 Thus, in conclusion, in this first interim analysis from EMPRISE, the investigative team showed that compared with sitagliptin the initiation of empagliflozin was associated with a decreased risk of hospitalization for heart failure among patients with Type 2 diabetes as treated in routine care with and without a history of cardiovascular disease. Dr Gregory Hundley:       Well, now we're going to turn our attention to red meat. And this next study was entitled, The Consumption of Meat, Fish, Dairy Products, Eggs, and Risk of Ischemic Heart Disease. It's a Perspective study of 7,198 incident cases among 409,885 participants in the Pan European Epic Cohort. And the corresponding author is Professor Timothy Key from The University of Oxford.                                                 Some of the background here, met analysis of previous prospective studies have suggested that intake of processed meat maybe associated with a higher risk of ischemia heart disease whereas, unprocessed red meat might not. For dairy products and eggs, systematic reviews of prospective studies have reported no consistent evidence that higher intakes are associated with a higher risk of ischemic heart disease.                                                 Other studies have shown that fatty fish consumption may reduce the risk of ischemic heart disease, it is a rich source of long chain N3 fatty acids. And meta-analysis has suggested even an inverse association between overall fish consumption and mortality from ischemic heart disease.                                                 So, hear in this cohort: we're going to evaluate all of these. Accordingly Key, and his co-authors report the relationships of these foods with risk of ischemic heart disease in the European prospective investigation into cancer and nutrition, the EPIC study, and that again is a cohort of a half million men and women from nine European countries followed for 12 years to examine the association between the intake of animal foods and the occurrence of ischemic heart disease.                                                 The author's found that higher consumption of red, unprocessed and processed meat was positively associated with the risk of ischemic heart disease. None of the other animal foods examined were positively associated with this risk. And intakes of fatty fish, yogurt, cheese and eggs were modestly, inversely associated with the risk.                                                 In addition, the red and processed meat were associated with plasma non-HDL cholesterol and systolic blood pressure. And this finding is of interest as possibly these other variables could serve as mediator of the association between red or processed meat and future ischemic heart disease. It is important to note that while these results are of interest to those concerned with the future adverse cardiovascular effects related to the consumption of red meat, one cannot infer causality and other studies would need to be designed to address causal relationships.                                                 The last paper that I'm going to present during the coffee gulp, emanates from the basic science arena. And it is entitled The “Shear-Induced CCN1 Promotion of Atheroprone Endothelial Phenotypes and Arthrosclerosis. And the corresponding author is Dr Fan-E Mo from the National Cheng Kung University College of Medicine. Dr Gregory Hundley:       The matricellular protein CCN1 has been implicated in arthrosclerosis based on its expression in arterial segments with evidence of arthrosclerosis. And this study evaluated the relationship between sheer stress, both laminar and oscillatory at the site of atherosclerotic liaisons and molecular markers of pathophysiologic process involved in the progression of arthrosclerosis.                                                 The authors found that sheer induced CCN1 and its receptor integrin, alpha six, beta one, instigate atheroprone phenotypic changes in endothelial cells via activating NF kappa beta. Because the activation of NF kappa beta further up regulates the expression of CCN1, alpha six, and beta one, atheroprone flow creates a positive feedback to sustain atherogenesis.                                                 In addition, disrupting CCN1, alpha 6 beta one engagement by a specific CCN1 mutation, or by a peptide antagonist unhindered atherogenesis in mice. So what are the clinical implications of these findings? That's something Carolyn would ask me. Well, it appears that CCN1 alpha 6 beta one engagement represents a novel therapeutic target for arthrosclerosis.                                                 These data demonstrate a causative role of CCN1 in atherosclerosis via modulating endothelial phenotypes. And CCN1 binds to its receptor integrin alpha 6 beta one to activate NF kappa beta, thereby instigating a vicious cycle to persistently promote atherogenesis. Perhaps in the future T1 me medics may further be optimized to treat arthrosclerosis.                                                 Well everyone, that concludes the first portion of this June 18 edition of Circulation on the Run and now it's time to move on to Carolyn's discussion of our featured paper. Dr Carolyn Lam:                Cardiovascular disease remains the major cause of death in kidney transplant recipients. And today's featured paper has important implications for the management of this cardiovascular risk following kidney transplantation. I'm so excited to be discussing it, and I'm going to let the corresponding author Dr Toby Coates from Royal Adelaide Hospital tell us all about it, and so happy to also welcome our editorialist Dr Patrick Mark from University of Glasgow.                                                 Toby, could you please tell us what inspired you to do this remarkable study? Dr Toby Coates:                We're very interested in obviously our patients surviving as long as they possible can after kidney transplantation. And we noticed that many of them having had a successful kidney transplant, still had functioning AV fistulas. Now of course the AV fistula, is a connection between the artery and the vein that enabled us to access the circulation after hemodialysis. Which around the world is probably the most, is the most common form of dialysis practice performed.                                                 So many of these patients sustained 20 years down the track after successful transplants still had these very large functioning left to right shunts, on the basis of their dialysis history. So we had a couple of patients who developed quite severe cardiac failure and we noticed that when we ligated the AV fistula, their back got dramatically better.                                                 So, as a consequence of that, we went to look at the ligature and we couldn't find any randomized control trial that told us what the best thing was to do, post-transplant with these fistulas. So we decided that what we would do be use the state of the art cardiac magnetic resonance imaging, or cardiac MRI to assist the cardiac function with myocardium thickness in our patients and then randomize a group of stable transplant patients to ligation or not.                                                 And then follow that up with cardiac MRI six months down the track to see what happened. And so that was the basis of the study that we performed. The first randomized controlled trial of the effect of ligation of the AV fistula on the left ventricular mass, that was the prominent one for trial. Dr Carolyn Lam:                You know, Toby, just to let you know right there, I thought it was so incredibly novel. So I'm a heart failure specialist and we know that shunts are associated with high output cardiac failure, and yet, I personally had never questioned this, so I thought this is incredibly novel and it's important. But please, tell us all about the results. Dr Toby Coates:                We were delighted to say that there was a very significant reduction in the left ventricle mass. In fact, the main decrease was 22.1 grams compared to the control arm in whom the cardiac mass actually went up 1.2 grams. So, then we mobilized the body surface area, the reduction of the left ventricular mass index dropped by 11.8 grams per metered square.                                                 Now, this is quite remarkable for me doing the study because I've never seen an intervention, I've never seen an intervention where every single patient improved with the ligation, every single patient there was an improvement in the cardiac parameters. Never seen anything like it in the pre and post of the ventricular mass it really came down. So that was quite remarkable.                                                 And the second thing that really impressed me at the time, was the improvement in the BMP's, and we measured the brain maturated peptide, and being a methodologist that's clearly something that's of interest to us and we saw a substantial reduction. It's statistically significant reduction in BMP as well.                                                 The patient themselves, some of them recorded quite significant improvement in exercise tolerance afterwards. And we had, as I mentioned before in a couple of patients, not in the study but outside of the study, subsequently when they're presented with profound right heart failure, the ligation of the AV fistula made a huge difference to them symptomatically.                                                 So that was sort of confirming all of the things that we thought along the way. Pleasingly we didn't see any change in kidney function. So, we were concerned that there might have been on the basis of some non-controlled studies in the past, that there might have been a deterioration in the estimated glomerular filtration rate, or eGFR. We didn't see that.                                                 And we didn't see any significant change in the blood pressure either. Which is some of us have previously reported. Closing the fistula itself, is a very trivial procedure. It's usually done as an outpatient, so a day procedure. So it's not resulting in coming to the hospital. And the only complications, really were lots of local redness and some pain, potentially from the fistula where in the ligated.                                                 So, we thought this was remarkable. An outpatient procedure that could significantly reduce the left ventricular mass by 22.1 grams over the six month period that was associated with minimal side effects and complications. And when you think about that, that's sort of equivalent really to taking an anti-hypertensive medication for six months. That magnitude of reduction with ventricular mass which clearly from the patient's point of view is much preferable to adding more medication to an already over-burdened tablet loading in your patients with kidney transplants. So we were very pleased with that result altogether. Dr Carolyn Lam:                Thank you Toby, and we in turn were very pleased to be publishing this in Circulation. Likewise, Patty, if I may, I love your editorial. First, let me tell everybody who's listening out there. Go pick up the editorial and look at the figure. It is so cool. It shows pros and cons of arterial venous fistula ligation in these patients. But could you please share some thoughts Patty? I mean you covered the perspective just so well. Patrick Marks:                   I must give the credit to my co-author who actually drew the figure himself. So Chris Eaves rather myself. We were really impressed with the study and we're really delighted to write an editorial for it. It's just one of those studies that I have to say, you know, you kick yourself and you wish you'd done it. With all the world of observational data showing that creation of a fistula appears to be associated with an increase in LV mass obstruction by echo and angio and bicartic MR in smalls studies.                                                 But it's taken a long stat to move from that to actually doing a randomized control of ligating the fistula in people with you know, stable functioning transplants. We were really, really impressed with Toby and his team for undertaking this study. And until we'd gone through the results, they're really very impressive.                                                 The magnitude of reduction LV mass is very impressive and also the changing BMP was really nice to see. One of my comments of the study were, was interesting because as methodologists we are aware of the idea arteriovenous fistula as being the axis for dialysis. And we sometimes feel uncomfortable by ligating this because we know if the transplant was to fail, how much patients need a functioning fistula. And that's the one thing I'm still curious, like and I still offered some comments in the editorial were, that while there's doubt that the cardiovascular benefits demonstrated by Toby's study are really very impressive.                                                 I wondered about the implications out with the study came down the line, you know would there be some of these patients whose kidney transplant function would decline? And there may be regret of losing the access. We mentioned there is some inconvenience, it is an operative procedure to loosen the fistula. So there are some things to think about in the study, but overall, I can't help saying just how impressed I am that they managed to do this trial in a proper randomized, controlled trial form. It's really, really impressive in using the cardiac MR endpoint is it seems quite a secure way of assessing this. Dr Carolyn Lam:                Those are great points, Patty. Toby, any response to that. Dr Toby Coates:                Look it's really very interesting as a transplant pathologist for the last 20 years, one of the biggest, I guess it's a bit of a misconception. When a fistula has been present for 10 or 15 years and still there to come back and try and reuse it for dialysis access after that period of time, in my experience anyway, also very difficult to reuse those fistulas and the surgeons end up having to create a new one anyway.                                                 They frequently become quite aneurismal, they get very large and unsightly and the volume of the shunt is significant and often we find that as an access they don't work as well. So I personally don't have a huge concern about closing them. Now I agree with you, these patients were stable, longstanding and we assessed that the risk is, we need to go back onto hemodialysis was small.                                                 But you are absolutely right, I mean, it is possible that something could have come out of the blue and maybe a patient would be disappointed that that access that they'd had for so many years was no longer available. So that is, the caveat on the study, but thankfully so far out, some of these patients five or six years down the track, we haven't had anybody need to go back on dialysis, so it's been good. Dr Carolyn Lam:                Yeah, it really says to me as well, that patient selection is important exactly like you emphasized, and you, in the editorial Patty. But from a cardiology standpoint, too, are there plans to perhaps do studies with hard, clinical endpoints? What do you think are the next steps? Maybe I'll let Toby go first, then Patty. Dr Toby Coates:                We think now with this study done, the next thing is to have a larger study with significant cardiovascular endpoints. Which I obviously would be cardiac failure and acute coronary events. So the two things that would seem in my mind, and I think that needs to be multi-centered, preferable international if we can.                                                 And one of the really positive things about the highlight from the American Heart Association is that we've had people reach out to us from France and all around the globe saying that they'd be interested in participating, you know in a multi-centered trial. So, I think that's what we need to do, and clearly you don't it’ll have to be a constant endpoint, or not. I'd be interested in Patty's thoughts about that, right if you had some guidelines and some suggestions.                                                 And then obviously would be randomized, controlled trial looking at those hard endpoints with probably some sidearms doing cardiac MRI as well, and potentially more heart functioning tests. So yes, I think this is just the beginning, we do need a hard endpoint trial to really nail this completely. Patrick Marks:                   Yeah, I'll just come in there and just come on to that Toby. I completely concur with what you said. I think there's been quite a provocative editorial a few years back, and suggesting that while there's lots of studies in chronic kidney disease, end stage renal disease, kidney transplant patients avoid LV mass, really it hasn't yet been translated into actually leading studies in the integration of LV mass and end stage renal failure haven't really yet translated into mortality benefits.                                                 And I think we need to move to a bigger study. It's really beautiful that you've been able to demonstrate LV mass falls naturally with ligation. And it's impressive that it just happens so consistently across your population in the intervention arm. But we need to move on to a longer trial with hard clinical endpoints. Certainly heart failure, certainly cardiovascular mortality, [be]cause there's plenty of reasons to believe that producing LV mass in these patients might have benefit both for heart failure, whether that's heart failure, heart injection fraction, or whatever, I'll leave that to Carolyn's judgment to help us with that.                                                 But also, if we can reduce LV mass and then we may be able to reduce arrhythmia burden which again is when these things we worry about in end stage renal disease, again, your answer for that is, that in addition to the heart endpoints you should be able to also add in some patient afforded outcomes in a larger study. Or something like an exercise tolerance quota of quality of life.                                                 All this has started has journey from the surrogate endpoint of left ventricular mass into a bigger outcome study and I can't wait to see how you get on with it. Dr Carolyn Lam:                I can't wait either. And I'm sure the audience is sharing all our enthusiasm as well. Thank you so much Toby and Patty. I really learned so much. You heard it right here on Circulation on the Run. Thank you for joining us this week. Don't forget to turn in again next week.                                                 This program is copyright American Heart Association 2019.  

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